Pyrrolidinone derivative compound

ABSTRACT

A compound represented by the following formula (12) useful as an intermediate for production of drug or agricultural chemical:  
                 
 
     (wherein R 21  to R 25  are each independently a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group of 1 to 4 carbon atoms, an alkoxy group of 1 to 4 carbon atoms, a perfluoroalkyl group of 1 to 4 carbon atoms, a cyano group, a nitro group, an amino group, a carboxyl group, a thiol group, an alkylthio group of 1 to 4 carbon atoms or a carbamoyl group) can be produced by reacting a compound represented by the formula (13):  
                 
 
     (wherein R 21  to R 25  have the same definitions as given above) with 1,1-cyclopropanedicarboxylic acid. The compound of the formula (12) is useful as a raw material for production of a pyrrolidinone compound useful as an active ingredient of drug.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention relates to a process for production of apyrrolidinone compound which is useful as, for example, a remedy forcentral nervous system disorders (e.g. schizophrenia, dementia, manicdepressive psychosis, anxiety neurosis, drug poisoning and ischemicencephtalopathy), diseases associated with immunodeficiency andcryptorrhea, peptic ulcer, diabetes and complications thereof, glaucoma,etc.; a 3-carboxy-1-substituted-2-pyrrolidinone compound which is auseful intermediate for production of the above pyrrolidinone compound;and a process for production of the3-carboxy-1-substituted-2-pyrrolidinone compound.

[0003] 2. Description of the Related Art

[0004] Pyrrolidinone compounds having a pyrrolidinone skeleton as thebasic structure, which are useful as, for example, a remedy for centralnervous system disorders (e.g. schizophrenia, dementia, manic depressivepsychosis, anxiety neurosis, drug poisoning and ischemicencephtalopathy), diseases associated with immunodeficiency andcryptorrhea, peptic ulcer, diabetes and complications thereof, glaucoma,etc., and processes for production of the compounds are disclosed in EPPublication No. 0668275A1 and Japanese Patent Application Kokai(Laid-Open) No. 40667/1997.

[0005] In producing the pyrrolidinone compounds according to the aboveprocesses, however, the number of steps is large and a reduction in thenumber of steps has been desired for the economic reason. There has alsobeen a problem of using a hydrogen-generating substance. There has alsobeen a problem that a corrosive substance must be used.

[0006] With respect to the process for production of a3-carboxy-1-phenyl-2-pyrrolidinone compound which is useful as anintermediate for production of the above pyrrolidinone compounds, thereare known, for example, a process by Danishefsky et al. described inOrg. Synth., 60, 66-71, 1981; and a process of hydrolyzing an estercompound obtained by a process described in Japanese Patent ApplicationKokai (Laid-Open) No. 40667/1997.

[0007] However, the former process uses, as a raw material,6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione which is expensive.Also, the latter process of hydrolyzing an ester compound is notpreferred for a safety reason because it may use a moisturesensitive/ignitive reagent in synthesis of the ester compound. None ofthese processes is satisfactory for industrial application.

SUMMARY OF THE INVENTION

[0008] An object of the present invention is to provide a process forproducing the above pyrrolidinone compound useful as a pharmaceuticallyactive ingredient, wherein the number of steps is smaller and neitherhydrogen-generating substance nor corrosive substance is used.

[0009] Another object of the present invention is to provide a processfor producing a 3-carboxy-1-phenyl-2-pyrrolidinone compound useful as anintermediate for production of the above pyrrolidinone compound usefulas a pharmaceutically active ingredient, without using any expensive rawmaterial.

[0010] Still another object of the present invention is to provide aprocess for producing the 3-carboxy-1-phenyl-2-pyrrolidinone withoutusing any moisture sensitive/ignitive reagent.

[0011] The pyrrolidinone compound obtained by the present process isrepresented by the following formula (1):

[0012] wherein R is an alkyl group of 1 to 12 carbon atoms or asubstituent represented by the formula (2):

[0013] (wherein R² is a hydrogen atom, a halogen atom, an alkyl group of1 to 4 carbon atoms, an alkoxy group of 1 to 4 carbon atoms, aperfluoroalkyl group of 1 to 4 carbon atoms, a hydroxyl group, a cyanogroup, an amino group, a nitro group, a carbamoyl group, a thiol group,an alkylthio group of 1 to 4 carbon atoms or a carboxyl group; p is aninteger of 1 to 5; when p is 2 or more, each R² independently has thesame definition as given above; and j is an integer of 0 to 2), and Q isa substituent represented by the formula (3a), (3b), (3c) or (3d):

[0014] {in the formula (3a), R³ and R⁴ are each independently a hydrogenatom or an alkyl group of 1 to 4 carbon atoms, and R³ and R⁴ may bond toeach other to form a morpholine ring; in the formula (3b), m and n areeach independently an integer of 1 to 4, X is a hydrogen atom, ahydroxyl group, a cyano group, a carbamoyl group, a halogen atom or analkyl group of 1 to 4 carbon atoms, and Y is a hydrogen atom, an alkylgroup of 1 to 4 carbon atoms, a perfluoroalkyl group of 1 to 4 carbonatoms, or a substituted or unsubstituted phenyl group; in the formula(3c), W is an alkyl group of 1 to 4 carbon atoms, a substituted orunsubstituted phenyl group, or an alkyl group of 1 to 2 carbon atomssubstituted with a substituted or unsubstituted phenyl group, and in theformula (3d), m and n are each independently an integer of 1 to 4, Z isa hydrogen atom, an alkyl group of 1 to 18 carbon atoms, a substitutedor unsubstituted phenyl group, an alkyl group of 1 to 2 carbon atomssubstituted with a substituted or unsubstituted phenyl group, or asubstituent represented by the formula (4):

—(CH₂)_(k)—OR⁵   (4)

[0015] (wherein k is an integer of 2 to 3; and R⁵ is a hydrogen atom, analkyl group of 1 to 3 carbon atoms, an alkenyl group of 2 to 3 carbonatoms or an alkynyl group of 2 to 3 carbon atoms)}.

[0016] The compound of the formula (1) is useful as, for example, aremedy for central nervous system disorders (e.g. schizophrenia,dementia, manic depressive psychosis, anxiety neurosis, drug poisoningand ischemic encephtalopathy), diseases associated with immunodeficiencyand cryptorrhea, peptic ulcer, diabetes and complications thereof,glaucoma, etc.

[0017] The present process for producing the pyrrolidinone compound ofthe formula (1) includes a step of reacting a compound represented bythe formula (5):

[0018] (wherein R¹ has the same definition as given above) with an aminederivative represented by the formula (6a), (6b), (6c) or (6d):

[0019] (in the formula (6a), R³ and R⁴ have the same definitions asgiven above; in the formula (6b), X, Y, m and n have the samedefinitions as given above; in the formula (6c), W has the samedefinition as given above; and in the formula (6d), Z, m and n have thesame definitions as given above} in the presence of formaldehyde toproduce a pyrrolidinone compound of the formula (1).

[0020] The 3-carboxy-1-phenyl-2-pyrrolidinone compound which is usefulas a starting material (an intermediate) for production of thepyrrolidinone compound of the formula (1), is represented by thefollowing formula (12) and is one of the compounds of the formula (5):

[0021] (wherein R²¹ to R²⁵ are each independently a hydrogen atom, ahydroxyl group, a halogen atom, an alkyl group of 1 to 4 carbon atoms,an alkoxy group of 1 to 4 carbon atoms, a perfluoroalkyl group of 1 to 4carbon atoms, a cyano group, a nitro group, an amino group, a carboxylgroup, a thiol group, an alkylthio group of 1 to 4 carbon atoms or acarbamoyl group).

[0022] The compound of the formula (12) is useful as an intermediate forproduction of the pyrrolidinone compound of the formula (1) or as anintermediate for production of an agricultural chemical.

[0023] The compound of the formula (12) can be obtained by reacting acompound of the formula (13):

[0024] (wherein R²¹ to R²⁵ have the same definitions-as given above)with 1,1-cyclopropanedicarboxylic acid.

[0025] According to the present invention, there can be provided aprocess for producing a pyrrolidinone compound of the formula (1),wherein the number of steps is efficiently reduced and neitherhydrogen-generating substance nor corrosive substance is used.

[0026] According to the present invention, there can also be provided a3-carboxy-1-phenyl-2-pyrrolidinone compound which is useful as anintermediate for production of the pyrrolidinone compound of the formula(1); and a process for producing the 3-carboxy-1-phenyl-2-pyrrolidinonecompound without using any expensive raw material or without using anymoisture sensitive/ignitive reagent.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

[0027] The production processes of the present invention are describedin detail below.

[0028] The present process for production of the compound of the formula(1) includes, as mentioned previously, a step of reacting a compound ofthe formula (5) with one of the compounds of the formulas (6a) to (6d)in the presence of formaldehyde.

[0029] Preferably in the present process, a pyrrolidinone compound ofthe formula (1) {wherein R¹ is a substituent represented by the formula(2a):

[0030] (wherein R^(2a) is a hydrogen atom or a halogen atom; p is aninteger of 1 to 5; when p is 2 or more, each R^(2a) independently hasthe same definition as given above; and j^(a) is 0), and Q is asubstituent represented by the formula (7):

[0031] (wherein m and n are each independently an integer of 1 to 4; kis an integer of 2 to 3; and R is a hydrogen atom, an alkyl group of 1to 3 carbon atoms, an alkenyl group of 2 to 3 carbon atoms or an alkynylgroup of 2 to 3 carbon atoms)} is produced by reacting a compound of theformula (5) {wherein R¹ is a substituent represented by the formula (2a)(wherein R^(2a), p and j^(a) have the same definitions as given above)}with an amine derivative represented by the formula (6d) {wherein Z is asubstituent represented by the formula (4) (wherein k and R⁵ have thesame definitions as given above)} in the presence of formaldehyde.

[0032] Also preferably in the present process, a pyrrolidinone compoundof the formula (1) {wherein R¹ is a 4-chlorophenyl group and Q is asubstituent represented by the formula (8):

[0033] (wherein R⁶ is an alkyl group of 1 to 3 carbon atoms)} isproduced by reacting a compound of the formula (5) (wherein R¹ is a4-chlorophenyl group) with an amine derivative represented by theformula (9):

[0034] (wherein R⁶ has the same definition as given above) in thepresence of formaldehyde.

[0035] The amine derivative represented by the formula (9) is preferablyan amine derivative of the formula (9) wherein R⁶ is a methyl group.

[0036] In the general formula (1), “alkyl group of 1 to 3 carbon atoms”refers to a methyl group, an ethyl group, an n-propyl group or anisopropyl group; “alkyl group of 1 to 4 carbon atoms” refers to eachgroup mentioned above, an n-butyl group, a sec-butyl group, a tert-butylgroup, an isobutyl group or the like; “alkyl group of 1 to 12 carbonatoms” refers to each group mentioned above, a pentyl group, a hexylgroup, a heptyl group, an octyl group, a nonyl group, a decyl group, anundecyl group, a dodecyl group or the like; “alkyl group of 1 to 18carbon atoms” refers to each group mentioned above, a tridecyl group, atetradecyl group, a pentadecyl group, a hexadecyl group, a heptadecylgroup, an octadecyl group or the like; “alkenyl group of 2 to 3 carbonatoms” refers to a vinyl group, an allyl group, a 1-propenyl group, anisopropenyl group or the like; “alkynyl group of 2 to 3 carbon atoms”refers to an ethynyl group, a 1-propynyl group, a 2-propynyl group orthe like; “halogen atom” refers to a fluorine atom, a chlorine atom, abromine atom or an iodine atom; “alkoxy group of 1 to 4 carbon atoms”refers to a methoxy group, an ethoxy group, an n-propoxy group, anisopropoxy group, a butoxy group or the like; “perfluoroalkyl group of 1to 4 carbon atoms” refers to a trifluoromethyl group, a pentafluoroethylgroup, a heptafluoropropyl group, a nonafluorobutyl group or the like;“alkylthio group of 1 to 4 carbon atoms” refers to a methylthio group,an ethylthio group, a propylthio group, a butylthio group or the like;“substituted phenyl group” refers to a phenyl group substituted with ahalogen atom(s), an alkyl group(s) of 1 to 4 carbon atoms, an alkoxygroup(s) of 1 to 4 carbon atoms, a perfluoroalkyl group(s) of 1 to 4carbon atoms or the like; and “alkyl group of 1 to 2 carbon atomssubstituted with a phenyl group” refers to a benzyl group, a phenethylgroup or the like.

[0037] The production route of the present invention for the compound ofthe formula (1) is shown by the following reaction formula (1).

[0038] {wherein R¹ and Q have the same definitions as in the generalformula (1); and 6a, 6b, 6c and 6d have the same definitions as in thegeneral formulas (6a) to (6d)}.

[0039] As the formaldehyde used in the reaction of the reaction formula(1), there can be mentioned paraformaldehyde, trioxane, aqueoussolutions thereof, etc. The aqueous solution ordinarily has aconcentration of 5 to 50% by weight. The formaldehyde is used in anamount of 1 to 10 moles per mole of the compound of the general formula(5).

[0040] As the solvent used in the reaction, there can be mentionedwater; alcohols such as methanol, ethanol, isopropanol, butanol and thelike; ethers such as diethyl ether, dioxane, tetrahydrofuran, ethyleneglycol dimethyl ether and the like; aromatic hydrocarbons such asbenzene, toluene and xylene and the like; halogen-containinghydrocarbons such as dichloromethane, dichloroethane, chloroform and thelike; acetonitrile; and so forth. These solvents can be used singly orin admixture. The reaction may be conducted without using any solvent.

[0041] The reaction temperature may range from 0° C. to the boilingpoint of the solvent used, preferably from room temperature to 150° C.

[0042] The reaction time is not particularly restricted, but ispreferably 1 to 48 hours.

[0043] There is no particular restriction as to the order of mixing thecompound of the general formula (5), the amine derivative of the generalformula (6a), (6b), (6c) or (6d) and formaldehyde. They are mixed at onetime; or, the amine and formaldehyde are mixed first and then thecompound of the general formula (5) is added; or, the compound of thegeneral formula (5) and formaldehyde are mixed first and then the amineis added.

[0044] In the reaction of the reaction formula (1), there is a case whena 3-methylene form of the compound of the formula (5), represented bythe following general formula (10):

[0045] {wherein R¹ has the same definition as in the general formula(1)} is formed as an intermediate. This intermediate may be reacted withthe amine of the general formula (6a), (6b), (6c) or (6d).

[0046] This reaction may be conducted in an equimolar ratio. The aminemay be used in excess.

[0047] As the solvent used in the reaction, there can be mentionedwater; alcohols such as methanol, ethanol, isopropanol, butanol and thelike; ethers such as diethyl ether, dioxane, tetrahydrofuran, ethyleneglycol dimethyl ether and the like; aromatic hydrocarbons such asbenzene, toluene and xylene and the like; halogen-containinghydrocarbons such as dichloromethane, dichloroethane, chloroform and thelike; ketones such as acetone, methyl ethyl ketone and the like;acetonitrile; and so forth. These solvents can be used singly or inadmixture. The reaction may be conducted without using any solvent.

[0048] The reaction temperature may range from 0° C. to the boilingpoint of the solvent used, preferably from room temperature to 150° C.

[0049] The reaction time is not particularly restricted, but ispreferably 1 to 48 hours.

[0050] In the post-treatment after the above reaction, a purificationmethod ordinarily used, such as column chromatography, recrystallizationor the like can be used.

[0051] The compound of the formula (5) is preferably a compound of theformula (5) wherein R¹ is represented by the formula (2) (wherein R² andp have the same definitions as given above, and j is 0), or a saltthereof; more preferably a compound of the formula (5) wherein R¹ is a4-chlorophenyl group.

[0052] The compound of the formula (5) can be obtained by a knownprocess, for example, by hydrolyzing, with an acid or an alkali, acompound of the general formula(11):

[0053] (wherein R¹ has the same definition as in the formula (1), and Ais an alkyl group of 1 to 4 carbon atoms, a substituted or unsubstitutedphenyl group, or an alkyl group of 1 to 2 carbon atoms substituted witha substituted or unsubstituted phenyl group), the compound of theformula (11) being obtained by a process described in EP Publication No.0668275A1 or Japanese Patent Application Kokai (Laid-Open)No.40667/1997.

[0054] In the above reaction, there can ordinarily be used, as the acid,an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoricacid or the like; and there can be mentioned, as the alkali, sodiumhydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate,potassium carbonate, etc.

[0055] The amount of the acid or alkali used is 0.1 to 100 moles,preferably 1 to 10 moles per mole of the compound of the formula (11).

[0056] The reaction may be conducted in the presence of a phase-transfercatalyst.

[0057] As the solvent used in the reaction, there can be mentionedwater; alcohols such as methanol, ethanol, isopropanol, butanol and thelike; ethers such as diethyl ether, dioxane, tetrahydrofuran, ethyleneglycol dimethyl ether and the like; aromatic hydrocarbons such asbenzene, toluene and xylene and the like; halogen-containinghydrocarbons such as dichloromethane, dichloroethane, chloroform and thelike; acetonitrile; and so forth. These solvents can be used singly orin admixture.

[0058] The reaction temperature may range from 0° C. to the boilingpoint of the solvent used, preferably from room temperature to 150° C.

[0059] The reaction time is not particularly restricted, but ispreferably 1 to 48 hours.

[0060] The carboxylic acid obtained can be used in the next reaction asit is or in the form of a salt thereof.

[0061] A compound of the following formula (12) as one of the compoundsof the formula (5):

[0062] (wherein R²¹ to R²⁵ are each independently a hydrogen atom, ahydroxyl group, a halogen atom, an alkyl group of 1 to 4 carbon atoms,an alkoxy group of 1 to 4 carbon atoms, a perfluoroalkyl group of 1 to 4carbon atoms, a cyano group, a nitro group, an amino group, a carboxylgroup, a thiol group, an alkylthio group of 1 to 4 carbon atoms or acarbamoyl group) can be obtained by reacting a compound represented bythe formula (13):

[0063] {wherein R²¹ to R²⁵ have the same definitions as in the formula(12)} with 1,1-cyclopropanedicarboxylic acid.

[0064] This process, as compared with the known process mentioned above,has a merit in using neither expensive raw material nor moisturesensitive/ignitive reagent.

[0065] In the above process, it is preferred that R²¹, R²², R²⁴ and R²⁵are each a hydrogen atom and R²³ is a chlorine atom or a bromine atom;and it is more preferred that R²¹, R²², R²⁴ and R²⁵ are each a hydrogenatom and R²³ is a chlorine atom.

[0066] In the formulas (12) and (13), the halogen atom includes afluorine atom, a chlorine atom, a bromine atom and an iodine atom.

[0067] As the lower alkyl group of 1 to 4 carbon atoms, there can bementioned, for example, a methyl group, an ethyl group, an n-propylgroup, an isopropyl group, an n-butyl group, an isobutyl group, asec-butyl group and a tert-butyl group.

[0068] As the lower alkoxy group of 1 to 4 carbon atoms, there can bementioned, for example, a methoxy group, an ethoxy group, a propoxygroup, an isopropoxy group, an n-butoxy group, an isobutoxy group, asec-butoxy group and a tert-butoxy group.

[0069] As the perfluoroalkyl group of 1 to 4 carbon atoms, there can bementioned, for example, a trifluoromethyl group, a pentafluoroethylgroup, a heptafluoropropyl group, a heptafluoroisopropyl group and anonafluorobutyl group.

[0070] As the lower alkylthio group of 1 to 4 carbon atoms, there can bementioned, for example, a methylthio group, an ethylthio group, ann-propylthio group, an isopropylthio group, an n-butylthio group, anisobutylthio group, a sec-butylthio group and a tert-butylthio group.

[0071] The reaction of the compound of the formula (13) with1,1-cyclopropanedicarboxylic acid can be conducted in the presence orabsence of a solvent. As the solvent, there can be mentioned aromatichydrocarbons such as benzene, toluene, xylene and the like; ethers suchas diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,ethylene glycol dimethyl ether and the like; alcohols such as methanol,ethanol, propanol and the like; aprotic polar solvents such asdimethylformamide, dimethyl sulfoxide and the like; halogen-containingsolvents such as methylene chloride, chloroform, dichloroethane and thelike; carboxylic acid esters such as ethyl acetate, ethyl propionate andthe like; carboxylic acids such as formic acid, acetic acid, propionicacid and the like; water; acetone; methyl ethyl ketone; andacetonitrile. These solvents can be used singly or in admixture.

[0072] The proportions of the compound of the formula (13) and1,1-cyclopropanedicarboxylic acid should be determined in view of theirreactivity, the formation of by-products and the economy of thereaction; however, the compound of the formula (13) is used in an amountof generally 0.1 to 10 moles, preferably 0.3 to 3 moles, more preferably0.6 to 1.5 moles per mole of 1,1-cyclopropanedicarboxylic acid.

[0073] The reaction temperature, when a solvent is used, may range fromabout room temperature to the reflux temperature, preferably from 60° C.to 100° C., more preferably from 70° C. to 95° C. and, when no solventis used, may range from about room temperature to about the meltingpoint of reaction substrates used.

EXAMPLES

[0074] The present invention is described more specifically below withreference to Examples. However, the present invention is not restrictedby these Examples.

Example 1

[0075] Production of 3-carboxy-1-(4-chlorophenyl)-2-pyrrolidinone

[0076] 2.0 g of 1,1-cyclopropanedicarboxylic acid and 2.9 g of4-chloroaniline were added to 2.7 g of water. The mixture was stirred at80° C. for 20 hours.

[0077] To the reaction mixture were added 20 ml of a 25% aqueous NaOHsolution and 20 ml of ethyl acetate, followed by thorough stirring. Theaqueous layer was washed with ethyl acetate and then made acidic withhydrochloric acid. The resulting crystals were collected by filtration,then washed with water, and dried to obtain 2.2 g of an intendedcompound at a yield of 59.7%.

[0078] Melting point: 170° C. (decomposed)

[0079]¹H-NMR (DMSO, δ ppm): 2.2-2.4 (2H, m), 3.61 (1H, t), 3.8-3.95 (2H,m), 7.4-7.5 (2H, m), 7.65-7.75 (2H, m)

Example 2

[0080] Production of 1-(4-bromophenyl)-3-carboxy-2-pyrrolidinone

[0081] 30 g of 1,1-cyclopropanedicarboxylic acid and 50 g of4-bromoaniline were added to 50 ml of acetonitrile, followed byrefluxing for 7 hours with heating and stirring.

[0082] The reaction mixture was subjected to solvent removal underreduced pressure. To the residue were added an aqueous sodiumhydrogencarbonate solution and ethyl acetate, and the mixture wasstirred thoroughly. The aqueous layer was washed with ethyl acetate,then made acidic with hydrochloric acid, and subjected to extractionwith ethyl acetate. The organic layer was dried over anhydrous magnesiumsulfate and then concentrated under reduced pressure. The resultingconcentrate was sludged with diethyl ether to obtain 32.8 g of anintended compound at a crude yield of 50.2%.

[0083]¹H-NMR (CDCl₃, δ ppm): 2.39-2.68 (2H, m), 3.66 (1H, t), 3.85 (2H,m), 7.51 (4H, s)

Example 3

[0084] Production of3-carboxy-1-(3-trifluoromethylphenyl)-2-pyrrolidinone

[0085] 10.0 g of 1,1-cyclopropanedicarboxylic acid and 12.4 g of4-trifluoromethylaniline were added to 15 ml of acetonitrile, followedby refluxing for 7 hours with heating and stirring. The subsequentoperation was conducted in the same manner as in Example 2 to obtain 7.1g of an intended compound at a yield of 38.8%.

[0086]¹H-NMR (CDCl₃, δ ppm): 2.43-2.67 (2H, m), 3.73 (1H, t), 3.97 (2H,t), 7.47-7.54 (2H, m), 7.75-7.87 (2H, m)

Reference Example 1

[0087] Production of 3-carboxy-1-(4-chlorophenyl)-2-pyrrolidinone

[0088] 61.8 g of 1-(4-chlorophenyl)-3-ethoxycarbonyl-2-pyrrolidinone wasmixed with 45 g of ethanol. Thereto was added a solution of 46.1 g ofsodium hydroxide dissolved in 100 ml of water, followed by mixing. Themixture was once made into a complete solution, after which a largeamount of crystals appeared.

[0089] Thereto was added water. The crystals were collected byfiltration and washed with diethyl ether. To the filtrate was addeddiethyl ether, followed by stirring. The aqueous layer was separated.This aqeuous layer and the crystals were combined and made acidic withhydrochloric acid with thorough stirring. The crystals were collected byfiltration and washed with water to obtain 52.5 g of3-carboxy-1-(4-chlorophenyl)-2-pyrrolidinone.

[0090] Melting point: 170° C. (decomposed)

[0091]¹H-NMR (DMSO, δ ppm): 2.2-2.4 (2H, m), 3.61 (1H, t), 3.8-3.95 (2H,m), 7.4-7.5 (2H, m), 7.65-7.75 (2H, m)

[0092] This spectrum data corresponded with that of the compoundobtained by reacting p-chloroaniline with6,6-dimethyl-5,7-dioxyaspiro[2,5]octane-4,8-dione according to themethod described in Org. Synth., 60, 66-71, 1981.

Example 4

[0093] Production of1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazine-1-yl]methyl-2-pyrrolidinone

[0094] 3.0 g of 1-(4-chlorophenyl)-3-carboxy-2-pyrrolidinone and 2.32 gof 4-(2-methoxyethyl)piperazine were mixed with 6 ml of methanol.Thereto was added 0.465 g of 80% paraformaldehyde. The mixture wassubjected to a reaction for 10.5 hours under refluxing and then cooledto room temperature. Thereto was added 10 ml of methanol, and theinsolubles were removed by filtration. The filtrate was concentratedunder reduced pressure. The residue was mixed with 15 ml of water. Theresulting crystals were collected by filtration and washed with 3 ml of95% aqueous methanol twice to obtain 3.42 g of1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazine-1-yl]methyl-2-pyrrolidinone.

[0095] Melting point: 103-105° C.

[0096]¹H-NMR (CDCl₃, δ ppm): 2.01-2.12 (1H, m), 2.29-2.62 (12H, m),2.78-2.94 (2H, m), 3.35 (3H, s), 3.51 (2H, t),3.74-3.80 (2H, m), 7.32(2H, d), 7.59 (2H, d)

Reference Example 2

[0097] Production of 1-(4-chlorophenyl)-3-methylene-2-pyrrolidinone

[0098] 1.56 g of 1-(4-chlorophenyl)-3-carboxy-2-pyrrolidinone was mixedwith 7 ml of methanol. Thereto were added 0.26 g of 75% paraformaldehydeand 0.75 g of 4-methoxypiperidine. The mixture was refluxed for 2 hours.The reaction mixture was concentrated to dryness. The residue waspurified by silica gel column chromatography using chloroform (asolvent) to obtain 0.85 g of1-(4-chlorophenyl)-3-methylene-2-pyrrolidinone.

[0099] Melting point: 119-120° C.

[0100]¹H-NMR (CDCl₃, δ ppm): 2.87-2.94 (2H, m), 3.83 (2H, t), 5.46 (1H,t), 6.14 (1H, t), 7.32-7.37 (2H, m), 7.67-7.73 (2H, m)

Reference Example 3

[0101] Production of1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazine-1-yl]methyl-2-pyrrolidinone

[0102] 0.85 g of 1-(4-chlorophenyl)-3-methylene-2-pyrrolidinone and 0.71g of 4-(2-methoxyethyl)piperazine were mixed with 3 ml of acetonitrile.The mixture was refluxed for 3.5 hours. The reaction mixture wasconcentrated to dryness. The residue was purified by silica gel columnchromatography using a mixed solvent (chloroform/methanol=20/1) toobtain 1.1 g of1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazine-1-yl]methyl-2-pyrrolidinone.

[0103] Melting point: 103-105° C.

[0104]¹H-NMR (CDCl₃, δ ppm) : 2.01-2.12 (1H, m), 2.29-2.62 (12H, m),2.78-2.94 (2H, m), 3.35 (3H, s), 3.51 (2H, t), 3.74-3.80 (2H, m) 7.32(2H, d), 7.59 (2H, d)

Reference Example 4

[0105] Production of1-(4-bromophenyl)-3-[4-(2-methoxyethyl)piperazine-1-yl]methyl-2-pyrrolidinone

[0106] 1.31 g of 1-(4-bromophenyl)-3-methylene-2-pyrrolidinone and 1.00g of 4-(2-methoxyethyl)piperazine were mixed with 5 ml of ethyleneglycol dimethyl ether. The mixture was refluxed for 6.5 hours and thencooled. Thereto was added water. The mixture was subjected to extractionwith ethyl acetate twice. The organic layer was dried over anhydrousmagnesium sulfate and then concentrated to obtain 1.91 g of1-(4-bromophenyl)-3-[4-(2-methoxyethyl)piperazine-1-yl]methyl-2-pyrrolidinone.

[0107]¹H-NMR (CDCl₃, δ ppm): 1.98-2.12 (1H, m), 2.29-2.41 (1H, m),2.53-2.63 (11H, m), 2.78-2.94 (2H, m), 3.35 (3H, s), 3.51 (2H, t),3.74-3.82 (2H, m), 7.46 (2H, d), 7.54 (2H, d)

Reference Example 5

[0108] Production of1-(4-bromophenyl)-3-[4-(2-methoxyphenyl)piperazine-1-yl]methyl-2-pyrrolidinone

[0109] 1.31 g of 1-(4-bromophenyl)-3-methylene-2-pyrrolidinone and 2.00g of 4-(2-methoxyphenyl)piperazine were mixed with 5 ml of ethyleneglycol dimethyl ether. The mixture was refluxed for 2 hours and thencooled. Thereto was added water. The mixture was subjected to extractionwith ethyl acetate twice. The organic layer was dried over anhydrousmagnesium sulfate and then concentrated to obtain an oily material. Theoily material was purified by silica gel column chromatography using amixed solvent of chloroform/methanol=40/1 to obtain 1.88 g of oily1-(4-bromophenyl)-3-[4-(2-methoxyphenyl)piperazine-1-yl]methyl-2-pyrrolidinone.

[0110]¹H-NMR (CDCl₃, δ ppm): 2.03-2.17 (1H, m), 2.34-2.46 (1H, m),2.60-3.20 (11H, m), 3.70-3.89 (2H, m), 3.87 (3H, s), 6.85-7.04 (4H, m),7.45-7.59 (4H, m)

Reference Example 6

[0111] Production of1-(4-bromophenyl)-3-pyrrolidinomethyl-2-pyrrolidinone

[0112] There were mixed 1.31 g of1-(4-bromophenyl)-3-methylene-2-pyrrolidinone, 2.00 g of4-(2-methoxyphenyl)piperazine and 5 ml of pyrrolidine. The mixture wasrefluxed for 1 hour and then cooled. Thereto was added water. Themixture was subjected to extraction with ethyl acetate twice. Theorganic layer was dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by silica gel columnchromatography using a mixed solvent of chloroform/methanol=40/1 toobtain 1.79 g of 1-(4-bromophenyl)-3-pyrrolidinomethyl-2-pyrrolidinone.

[0113]¹H-NMR (CDCl₃, δ ppm): 1.74-1.84 (4H, m), 2.01-2.15 (1H, m),2.34-2.45 (1H, m), 2.51-2.88 (6H, m), 2.94-3.00 (1H, m), 3.75-3.80 (2H,m), 7.46 (2H, d), 7.55 (2H, d)

What is claimed is:
 1. A process for producing a pyrrolidinone compound represented by the formula (1):

[wherein R¹ is an alkyl group of 1 to 12 carbon atoms or a substituent represented by the formula (2):

(wherein R² is a hydrogen atom, a halogen atom, an alkyl group of 1 to 4 carbon atoms, an alkoxy group of 1 to 4 carbon atoms, a perfluoroalkyl group of 1 to 4 carbon atoms, a hydroxyl group, a cyano group, an amino group, a nitro group, a carbamoyl group, a thiol group, an alkylthio group of 1 to 4 carbon atoms or a carboxyl group; p is an integer of 1 to 5; when p is 2 or more, each R² independently has the same definition as given above; and j is an integer of 0 to 2), and Q is a substituent represented by the formula (3a), (3b), (3c) or (3d):

{in the formula (3a), R³ and R⁴ are each independently a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, and R³ and R⁴ may bond to each other to form a morpholine ring; in the formula (3b), m and n are each independently an integer of 1 to 4, X is a hydrogen atom, a hydroxyl group, a cyano group, a carbamoyl group, a halogen atom or an alkyl group of 1 to 4 carbon atoms, and Y is a hydrogen atom, an alkyl group of 1 to 4 carbon atoms, a perfluoroalkyl group of 1 to 4 carbon atoms, or a substituted or unsubstituted phenyl group; in the formula (3c), W is an alkyl group of 1 to 4 carbon atoms, a substituted or unsubstituted phenyl group, or an alkyl group of 1 to 2 carbon atoms substituted with a substituted or unsubstituted phenyl group; and in the formula (3d), m and n are each independently an integer of 1 to 4, Z is a hydrogen atom, an alkyl group of 1 to 18 carbon atoms, a substituted or unsubstituted phenyl group, an alkyl group of 1 to 2 carbon atoms substituted with a substituted or unsubstituted phenyl group, or a substituent represented by the formula (4): —(CH₂)_(k)—OR⁵   (4) (wherein k is an integer of 2 to 3; and R⁵is a hydrogen atom, an alkyl group of 1 to 3 carbon atoms, an alkenyl group of 2 to 3 carbon atoms or an alkynyl group of 2 to 3 carbon atoms)}], which process includes a step of reacting a compound represented by the formula (5):

(wherein R¹ has the same definition as given above) with an amine derivative represented by the formula (6a), (6b), (6c) or (6d):

{in the formula (6a), R³ and R⁴ have the same definitions as given above; in the formula (6b), X, Y, m and n have the same definitions as given above; in the formula (6c), W has the same definition as given above; and in the formula (6d), Z, m and n have the same definitions as given above} in the presence of formaldehyde to produce a pyrrolidinone compound of the formula (1).
 2. A process according to claim 1, wherein a pyrrolidinone compound of the formula (1) {wherein R¹ is a substituent represented by the formula (2a):

(wherein R^(2a) is a hydrogen atom or a halogen atom; p is an integer of 1 to 5; when p is 2 or more, each R^(2a) independently has the same definition as given above; and j^(a) is 0), and Q is a substituent represented by the formula (7):

(wherein m and n are each independently an integer of 1 to 4; k is an integer of 2 to 3; and R⁵ is a hydrogen atom, an alkyl group of 1 to 3 carbon atoms, an alkenyl group of 2 to 3 carbon atoms or an alkynyl group of 2 to 3 carbon atoms)} is produced by reacting a compound of the formula (5) {wherein R¹ is a substituent represented by the formula (2a) (wherein R^(2a), p and j^(a) have the same definitions as give above)} with an amine derivative represented by the formula (6d) {wherein Z is a substituent represented by the formula (4) (wherein k and R⁵ have the same definitions as given above)} in the presence of formaldehyde.
 3. A process according to claim 2, wherein a pyrrolidinone compound of the formula (1) {wherein R¹ is a 4-chlorophenyl group and Q is a substituent represented by the formula (8):

(wherein R⁶ is an alkyl group of 1 to 3 carbon atoms)} is produced by reacting a compound of the formula (5) (wherein R¹ is a 4-chlorophenyl group) with an amine derivative represented by the formula (9):

(wherein R⁶ has the same definition as given above) in the presence of formaldehyde.
 4. A process according to claim 3, wherein the amine derivative is a compound of the formula (9) wherein R⁶ is a methyl group.
 5. A compound represented by the formula (5):

(wherein R¹ has the same definition as given above, with the proviso that R¹ is not any of a 2-methylphenyl group, a 3-trifluoromethylphenyl group, a 4-methoxyphenyl group and a 3,4-dichlorophenyl group); or a salt thereof.
 6. A compound of the formula (5) according to claim 5, wherein R¹ is represented by the formula (2) (wherein R² and p have the same definitions as given above, and j is 0); or a salt thereof.
 7. A compound of the formula (5) according to claim 5 or 6, wherein R¹ is a 4-chlorophenyl group; or a salt thereof.
 8. A process for producing a compound represented by the formula (12):

(wherein R²¹ to R²⁵ are each independently a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group of 1 to 4 carbon atoms, an alkoxy group of 1 to 4 carbon atoms, a perfluoroalkyl group of 1 to 4 carbon atoms, a cyano group, a nitro group, an amino group, a carboxyl group, a thiol group, an alkylthio group of 1 to 4 carbon atoms or a carbamoyl group) which process includes a step of reacting a compound represented by the formula (13):

(wherein R²¹ to R²⁵ have the same definitions as given above) with 1,1-cyclopropanedicarboxylic acid to produce a compound of the formula (12).
 9. A process according to claim 8, wherein R²¹, R²², R²⁴ and R²⁵ are each a hydrogen atom and R²³ is a chlorine atom or a bromine atom.
 10. A process according to claim 9, wherein R²³ is a chlorine atom. 